Surgery, chemotherapy and radiation therapy remain the standard weapons for the treatment of cancer. However, common human cancers are often not successfully treated with these modalities. Basic understanding of the immune system has provided new approaches and tools for cancer therapy. The goal of this program project is to develop effective treatments for cancer based on the exquisite specificity of the immune response. We have selected a restricted differentiation antigens expressed on cancer cells to target therapy. These differentiation antigens represent the closest approximation to realistic and specific targets on cancer cells. The theme of this program is based on several questions. 1) Can monoclonal antibodies (mAb) against restricted differentiation antigens localize and deliver therapeutic doses of nuclides to tumors? 2) Can mAbs with defined biological effector functions induce immune or inflammatory responses at tumor sites and lead to tumor responses? 3) Can immune responses be elicited against differentiation antigens, and can these responses alter the progression of cancer? During the past grant period, substantial progress was made in beginning to address these questions. First we have shown that certain mAbs localize to tumors, with high tumor:normal tissue ratios in patients with leukemia, colon, lung and renal cancer. Furthermore, some antibody-nuclide conjugates are efficiently internalized into target tumor cells (colon cancer and leukemia), opening the possibility of delivery of potent short range nuclides. Objective tumor regressions have been observed in patients with leukemia, lymphoma and neuroblastoma after treatment with mAb conjugated to nuclide. Second, treatment with mAb with defined effector functions has antitumor activity in metastatic melanoma, with a suggestion that cytokines, such as interleukin-2 or tumor necrosis factor-alpha, can increase potency of antitumor effects. Third, vaccination with a ganglioside antigen was shown to induce specific antibody responses in >80% of immunized patients, and a crucial role for immune adjuvants and carrier molecules was determined. Immune responses to the ganglioside in patients with stage III metastatic melanoma was shown to correlate significantly with survival. We plan to conduct therapeutic studies in patients with breast, colon, renal, and lung cancer, melanoma, and leukemia using mAb or vaccines. A new generation of genetically engineered mAb will be studied in clinical trials, including humanized, multimeric and single chain antibody constructs. Nuclides, including auger and alpha particle emitters will be conjugated to mAb for therapy. Novel antigens expressed in tumors will be targeted, including stromal and intracellular antigens. Finally, vaccines produced from purified antigens, peptides, or recombinant molecules, or as anti-idiotype mAb will be tested for immunogenicity against defined tumor antigens. The unifying theme of this project is to develop effective therapies for cancers based on targeting to restricted differentiation antigens on human cancer.